Abstract

Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal
models of neurodegenerative diseases. Such results were mainly associated with the
epigenetic modulation caused by HDACs, especially those from class I, via chromatin
deacetylation. However, other mechanisms may contribute to the neuroprotective effect
of HDAC inhibitors, since each HDAC may present distinct specific functions within
the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration
has been partially elucidated so far. The strategy to be adopted in promising therapeutics
targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection
by increasing the acetylation levels of α-tubulin with subsequent improvement of the
axonal transport, which is usually impaired in neurodegenerative disorders. On the
other hand, an induction of HDAC6 would theoretically contribute to the degradation
of protein aggregates which characterize various neurodegenerative disorders, including
Alzheimer’s, Parkinson’s and Hutington’s diseases. This review describes the specific
role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by
collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover,
structure, function, subcellular localization, as well as the level of HDAC6 expression
within brain regions are reviewed and compared to the other HDAC isoforms. In various
neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other
proteins seem to be a promising approach in understanding the modulation of HDAC6
activity.